Meibomian gland disease is the most common tear film and ocular surface disorder causing eye irritation. The incidence of the disease increases with age, and occurs in approximately 50% of patients with the skin disease, rosacea. A conservative estimate of the number of patients affected with this condition is 10 million in the United States alone. It has been reported that 15% of patients with ocular rosacea develop recurrent corneal epithelial erosions, a potentially sight-threatening problem.
Common complaints of patients suffering from meibomian gland disease include blurred or filmy vision, burning or foreign body sensations in the eye, photophobia, and pain severe enough to awaken the person from sleep. Although patients with this condition usually have normal production of aqueous tears by their lacrimal glands, their meibomian glands can atrophy and this is frequently accompanied by metaplasia of the ductal epithelium of these glands. Anterior erosion of the mucocutaneous junction of the eyelid is often noted, as well as eyelid and conjunctival infection, eyelid margin irregularity, corneal epithelial changes, and corneal vascularization.
The mechanisms responsible for the eyelid and ocular surface changes and irritation symptoms experienced by patients with meibomian gland disease were heretofore unknown. Therefore, previous treatments of meibomian gland disease were directed only to treatment of presumed infection of the eyelids or meibomian glands, or had particular disadvantages that made such treatments of little use for long periods of time. For example, patients with meibomian gland disease have been symptomatically treated with artificial tears, but these agents provide limited, if any, improvement. Topically applied steroids to the eyelids or ocular surface are effective as short-term pulse therapies. However, steroids are not good long-term solutions because of the potential side-effects e.g., cataract and glaucoma. Meibomian gland disease is currently not curable or reversible; therefore, patients with this condition must be treated for life.
Orally administered tetracyclines and tetracycline analogues (e.g., doxycycline and minocycline) having antibiotic activity are commonly and effectively used for prophylactic or therapeutic treatment of meibomian gland disease. The mechanism by which tetracyclines work in treating meibomian gland disease is not known, but some relief of symptoms has been reported. However, one disadvantage for using antimicrobially active tetracyclines or tetracycline analogues orally in the treatment of meibomian gland disease is that a high percentage of patients are unable to tolerate oral tetracyclines for extended periods of time. The intolerance to tetracyclines can manifest itself in gastrointestinal problems, e.g., epigastric pain, nausea, vomiting, and diarrhea, or other problems related to taking long-term oral antibiotics, such as mucosal candidiasis. At the present time there are no available long-term treatments of meibomian gland disease.
Recently, tetracycline and tetracycline analogues have been reported to have antimicrobial-inflammatory effects (e.g., reduction of IL-1 and nitric oxide production) and to inhibit synthesis and activation of MMPs. Tetracyclines have been reported to be effective in treating diseases where chronic inflammation and tissue destruction due to increased collagenase activity have been implicated. These diseases include rheumatoid arthritis, sterile corneal ulceration, and periodontitis.
Certain modifications of the chemical structure of tetracycline result in a tetracycline analogue which lacks antimicrobial activity. These non-antimicrobial, chemically modified tetracyclines (CMTs) retain their anti-inflammatory and anti-collagenolytic activities. Topical administration of antimicrobial tetracyclines or non-antimicrobial CMTs, or oral administration of non-antimicrobial CMTs represent a major advance in the therapy of patients having meibomian gland disease because both treatment modalities eliminate systemic toxicity and would allow lifetime administration of these therapeutic agents for this chronic disease.
The subject invention concerns a class of agents and methods of using those agents for treatment of a patient having meibomian gland disease, including relief of symptoms or conditions associated with the disease, such as ocular irritation, delayed tear clearance, or recurrent corneal epithelial erosion. More specifically, the subject invention concerns agents and methods for decreasing ocular irritation, and surface inflammation, improving tear clearance, reducing tear IL-1xcex1 concentration, or inhibiting IL-1xcex1-mediated matrix metalloproteinase activity which is increased in patients with meibomian gland disease or delayed tear clearance. The subject invention can thus be useful for reducing eye irritation, improving tear clearance, reducing IL-1xcex1 concentration in the tear fluid, or inhibiting MMP activity in the tear fluid of patients with delayed tear clearance and increased tear fluid IL-1xcex1.
In a preferred embodiment, the subject invention concerns use of an effective amount of a topically administered antimicrobial tetracycline or tetracycline analogue, or a non-antimicrobial analogue of tetracycline. Non-antimicrobial tetracycline analogues are commonly referred to and accepted in the scientific literature as xe2x80x9cchemically modified tetracyclinesxe2x80x9d (CMTs). These compounds, or compositions comprising those compounds, can be used for treating meibomian gland disease, ocular irritation associated with delayed tear clearance, or recurrent corneal epithelial erosion. Alternatively, CMTs can be administered orally for treating meibomian gland disease, ocular irritation associated with delayed tear clearance, or recurrent corneal epithelial erosion.